Process for preparing 4,4-dialkyl-6-halo-chromans or thiochromans useful as pharmaceutical intermediates

Abstract

A process of preparing intermediates useful in making compounds with retinoic acid-like activity is disclosed. The intermediates are halogenated chromans and thiochromans of the formula shown below and are prepared by the alkylation of a phenol or thiophenol with an alkene compound (the starting materials shown in the formula below), cyclization and halogenation. ##STR1## In the formula the symbols have the following meanings: R 1 and R 2 are C 1 to C 4 alkyl, R 3 is H or C 1 to C 4 alkyl, X is oxygen or sulfur, Y is a leaving group, and Z is chlorine, bromine or iodine.

What is claimed is: 
     
       1. A process of making a substituted chroman compound of formula IV ##STR8## in the sequence set forth below wherein X is oxygen, Z is chlorine, bromine or iodine, R 1  and R 2  are C 1  to C 4  alkyl, and R 3  is hydrogen or C 1  to C 4  alkyl, comprising, i) esterifying a compound of formula I with the hydroxyl function of an alcohol ##STR9## wherein R 3  is as defined in formula IV and the alcohol has from 1 to 6 carbon atoms   ii) alkylating the esterified product with a sufficient amount of a Grignard reagent, RMgX, wherein R is 1 to 4 carbon alkyl and X is chlorine or bromine to form the tertiary alcohol of formula VII, ##STR10##  iii) cyclizing the dialkylated product to form the bicyclic compound of formula III ##STR11## wherein R 1 , R 2  and R 3  and X are as defined in formula IV and   iv) halogenating said bicyclic compound to give a compound of formula IV.   
     
     
       2. The process of claim 1 wherein the halogenation in step iv is effected with bromine under electrophilic halogenation conditions to provide halogenation at the 6-position. 
     
     
       3. The process of claim 1 wherein the cyclization of the third step is effected with a protic add or a Lewis acid. 
     
     
       4. A process of making a substituted chroman compound of formula IV ##STR12## in the sequence set forth below wherein X is oxygen, Z is chlorine, bromine or iodine, R 1  and R 2  are methyl, and R 3  is hydrogen or C 1  to C 4  alkyl, comprising, i) esterifying a compound of formula I with the hydroxyl function of an alcohol ##STR13## wherein R 3  is as defined in formula IV and the alcohol has 1 carbon atom ii) alkylating the esterified product with a sufficient amount of a Grignard reagent, RMgX, wherein R is methyl and X is chlorine or bromine to form the tertiary alcohol of formula VII, ##STR14##  iii) cyclizing the dialkylated product in a solution of anhydrous aluminum chloride in nitromethane to form the bicyclic compound of formula III ##STR15## wherein R 1 , R 2  and R 3  and X are as defined in formula IV and     iv) halogenating said bicyclic compound under electrophilic halogenation conditions to give a compound of formula IV.   
     
     
       5. The process of claim 4 wherein X is oxygen, R 1  and R 2  are methyl, R 3  is hydrogen or methyl and Z is bromine. 
     
     
       6. The process of claim 5 wherein R 3  is hydrogen. 
     
     
       7. The process of claim 5 wherein the temperature of the bromination is maintained between -15° C. and 15° C. 
     
     
       8. The process of claim 7 wherein the temperature of the bromination is maintained between -8° C. and 0° C.